Healthy
Conditions
Brief summary
To assess the effects of lanthanum carbonate (FOSRENOL) or sevelamer carbonate (RENVELA) on the pharmacokinetics of oral calcitriol (ROCALTROL)
Interventions
DRUGCalcitriol
Calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.
DRUGLanthanum carbonate + Calcitriol
Lanthanum carbonate (1000 mg three times daily with meals for one day) + calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.
DRUGSevelamer carbonate + Calcitriol
Sevelamer carbonate (2400 mg three times daily with meals for one day) + calcitriol (1.0 microgram) single dose at lunch administered on Day 1 of the study period.
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers age 19-45 years inclusive at the time of consent. * Satisfactory medical assessment with no clinically significant or relevant abnormalities in medical history, physical examination, vital signs, electrocardiogram (ECG) and laboratory evaluation (hematology, biochemistry, urinalysis) as assessed by the Investigator. * No current or recurrent disease (e.g. cardiovascular, renal, liver, gastrointestinal (GI), malignancy or other conditions) that could affect the action, absorption or disposition of the investigational products utilized in this study, or could affect clinical or laboratory assessments.
Exclusion criteria
* Current or recurrent disease (eg, cardiovascular, renal, liver, GI, malignancy or other conditions) that could affect the action, absorption or disposition of the investigational products utilized in this study, or could affect clinical or laboratory assessments. * Current or relevant previous of physical or psychiatric illness, any medical disorder that could have required treatment or made the subject unlikely to fully complete the study, or any condition that presented undue risk from the investigational product or study procedures. * Current use of any medication with the exception of hormonal replacement therapy or hormonal contraceptives within 14 days of first dose of investigational product. * History of alcohol or other substance abuse within the last year. * A positive human immunodeficiency virus antibody screen, Hepatitis B surface antigen or Hepatitis C virus antibody screen. * Use of tobacco in any form * Donation of blood or blood products (eg, plasma or platelets) within 60 days prior to receiving the first dose of investigational product.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol | pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose | This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol | pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose | This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint. |
| Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol | pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose | This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint. |
Countries
United States
Participant flow
Pre-assignment details
Patients were randomly assigned to 1 of 6 treatment sequences which consisted of 3 treatment periods separated by a washout of 7 days. In each of the treatment periods subjects received lanthanum carbonate + calcitriol, sevelamer carbonate + calcitriol or calcitriol alone.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 1 Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention | 6 |
| Sequence 2 Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in third intervention | 7 |
| Sequence 3 Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention | 7 |
| Sequence 4 Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention | 7 |
| Sequence 5 Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in first intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Calcitriol (1.0 microgram) single dose at lunch for one day in third intervention | 7 |
| Sequence 6 Calcitriol (1.0 microgram) single dose at lunch for one day in first intervention, washout, Sevelamer carbonate (2400 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch) for one day in second intervention, washout, Lanthanum carbonate (1000 mg three times daily with meals) + Calcitriol (1 microgram single dose at lunch)for one day in third intervention | 7 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| First Intervention | Withdrew consent | 0 | 0 | 0 | 1 | 1 | 0 |
| Second Intervention | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 |
| Third Intervention | Withdrew consent | 0 | 0 | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence 2 | Sequence 3 | Sequence 4 | Sequence 1 | Sequence 5 | Sequence 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 7 Participants | 7 Participants | 6 Participants | 7 Participants | 7 Participants | 41 Participants |
| Age, Continuous | 30.0 years STANDARD_DEVIATION 6.24 | 30.9 years STANDARD_DEVIATION 5.52 | 28.4 years STANDARD_DEVIATION 7.28 | 27.7 years STANDARD_DEVIATION 8.94 | 31.0 years STANDARD_DEVIATION 8.52 | 30.4 years STANDARD_DEVIATION 10.41 | 29.8 years STANDARD_DEVIATION 7.55 |
| Region of Enrollment United States | 7 Participants | 7 Participants | 7 Participants | 6 Participants | 7 Participants | 7 Participants | 41 Participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 2 Participants | 5 Participants | 4 Participants | 3 Participants | 19 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 5 Participants | 1 Participants | 3 Participants | 4 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 38 | 2 / 40 | 3 / 38 |
| serious Total, serious adverse events | 0 / 38 | 0 / 40 | 0 / 38 |
Outcome results
Primary
Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol
This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time frame: pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Population: Pharmacokinetic set (PK) consists of subjects who received at least 1 dose of investigational product, had evaluable serum concentration-time profiles for calcitriol through 48 hours post-dosing on Day 1 of any treatment period and did not vomit between dosing and 10 hours post-dose on Day 1 of that treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Calcitriol (Lanthanum Carbonate) | Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol | 111 pg*h/ml |
| Calcitriol (Sevelamer Carbonate) | Area Under the Serum Concentration-time Curve (AUC 0-48) for Exogenous Calcitriol | -181 pg*h/ml |
Comparison: Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.p-value: 0.171Mixed Models Analysis
Comparison: Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.p-value: 0.024Mixed Models Analysis
Secondary
Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol
This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time frame: pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Population: PK set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Calcitriol (Lanthanum Carbonate) | Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol | -2.74 pg/ml |
| Calcitriol (Sevelamer Carbonate) | Maximum Plasma Concentration (Cmax) for Exogenous Calcitriol | -9.62 pg/ml |
Comparison: Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.p-value: 0.313Mixed Models Analysis
Comparison: Exogenous calcitriol was analyzed using a mixed linear effects model. This model contained sequence group, period, and treatment as fixed effects. The subject within sequence effect was included as a random effect.p-value: <0.001Mixed Models Analysis
Secondary
Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol
This shows the effect that lanthanum carbonate or sevelamer carbonate has on the pharmacokinetics of oral calcitriol. Exogenous calcitriol was the difference between total calcitriol value and the baseline exogenous calcitriol value at each sampling timepoint.
Time frame: pre-dose, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, and 48 hours post calcitriol dose
Population: PK set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Calcitriol (Lanthanum Carbonate) | Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol | 1.27 hours |
| Calcitriol (Sevelamer Carbonate) | Time of Maximum Plasma Concentration (Tmax) for Exogenous Calcitriol | 0.500 hours |
Comparison: Analysis for Tmax used the Hodges-Lehmann estimate for Wilcoxon's Signed Rank Test.p-value: 0.039Wilcoxon (Hodges-Lehmann)
Comparison: Analysis for Tmax used the Hodges-Lehmann estimate for Wilcoxon's Signed Rank Test.p-value: 0.305Wilcoxon (Hodges-Lehmann)